Abstract 5497: Venetoclax and dinaciclib elicit synergisticpreclinicalefficacy against high-risk B-cell leukemia
Authors: Ernesto Diaz-Flores, Holly Pariury, Mignon Loh
Journal: Cancer Research (2023)

Abstract Hypodiploid acute lymphoblastic leukemia (ALL) is an aggressive blood cancer with a poor prognosis despite intensive chemotherapy or stem cell transplant. Children and adolescents with positive end-of-induction minimal residual disease (MRD) have an overall survival lower than 30%. However, data regarding therapeutic alternatives for this disease is nearly non-existent, emphasizing the critical need for new or adjunctive therapies that can improve outcomes. We previously reported on the therapeutic efficacy of venetoclax (ABT-199) in hypodiploid B-ALL but with limitations as monotherapy (Diaz-Flores, Cancer Research, 2019). Accordingly, hypodiploid B-ALL patient derived xenografts treated with Venetoclax developed therapeutic resistance over time. To better understand the mechanism of resistance that arises following inhibition of BCL-2, we first generated a hypodiploid cell line (NALM-16) deficient in BCL-2. Given that BCL-2 plays an essential role in B-cell function standard CRISPR/Cas9 knockout strategies greatly impaired survival. We overcame this limitation by using a magnetic levitation system (the LeviCell by LevitasBio). Analysis of the surviving clones identified an increase in MCL1 (Fig. 1A). We then harnessed unbiased drug screen (&amp;gt;1800 bioactive compounds) followed by selection of synergistic drug combinations identified Dinaciclib as an efficient drug combination with Venetoclax in eliminating leukemic cells in vitro. Interestingly, mechanistic studies identified that Dinaciclib, through transcription regulation (RNApol II) significantly modulates MCL-1. Data using knock-outs and knock-ins of MCL-1 indicated how MCL-1 only becomes essential for survival when Venetoclax is present. Preclinical studies using patient derived xenografts indicated that, while none of the drug monotherapies achieved complete blast elimination, venetoclax + dinaciblib led to complete resolution of the leukemic burden within all solid organs analyzed (Fig. 1B). This combination therapy was relatively well tolerated. This study also indicates that high BCL-2 and MCL-1 levels with concomitant BIM, BAD and/or PUMA levels, represent biomarkers for response to this combination. In summary, our study identified a highly synergistic drug combination, venetoclax and dinaciclib, for the treatment of hypodiploid B ALL, an aggressive leukemia with few effective current therapies. Finally, the promising results presented in this study may prompt further studies to support the inclusion of hypodiploid and other B-ALL patients to clinical trials combining phase I/II drugs against BCL-2 (mainly venetoclax) and CDK9 (dinaciclib, alvocidib, flavopiridol, SNS-032) or MCL-1 (MIK-665). Citation Format: Ernesto Diaz-Flores, Holly Pariury, Mignon Loh. Venetoclax and dinaciclib elicit synergisticpreclinicalefficacy against high-risk B-cell leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5497.